Samarium(II)-promoted radical spirocyclization onto an aromatic ring

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Spirocyclic compounds are prevalent in natural products and pharmaceuticals, necessitating efficient synthetic strategies.
• Samarium(II) iodide (SmI2) is a powerful single-electron transfer reagent used in various organic transformations.
• Developing new methods for constructing spirocyclic frameworks remains a key challenge in organic synthesis.

Purpose of the Study:

• To develop a novel Samarium(II)-mediated spirocyclization reaction for constructing spirocyclic compounds.
• To explore the scope and limitations of this new synthetic methodology.
• To investigate the influence of aromatic ring substituents on the spirocyclization outcome.

Main Methods:

• Reaction of methyl 4-(4-oxoalkyl)benzoates with Samarium(II) iodide (SmI2) in the presence of isopropyl alcohol (i-PrOH) and hexamethylphosphoramide (HMPA).
• Utilizing SmI2-mediated reductive coupling and subsequent intramolecular cyclization.
• Varying the structure of the aromatic substrate and reaction conditions to assess efficiency and selectivity.

Main Results:

• Successful synthesis of methyl 1-alkyl-1-hydroxyspiro[4.5]dec-6-ene-8-carboxylates in moderate to high yields.
• Demonstrated versatility in synthesizing spiro[3.5], spiro[5.5], and sterically congested spiro[4.5] systems.
• Revealed that ester or amide groups on the aromatic ring promote spirocyclization, while a sulfonamide group directs ortho cyclization.

Conclusions:

• Samarium(II)-mediated spirocyclization is an effective strategy for accessing diverse spirocyclic architectures.
• The nature of the aromatic ring substituent critically controls the regioselectivity of the cyclization.
• This methodology provides a valuable tool for the synthesis of complex molecules with potential pharmaceutical applications.